Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. TGFβ Signaling: Canonical/SMAD, Non-Canonical/Non-SMAD, and Cross-Talk Pathways
3. Effects of TGFβ Signaling on Cell Cycle
4. Cell Cycle Dysregulation in Breast Cancer
5. CDK Inhibitor Therapy in Hormone Receptor Positive (HR+) Breast Cancer
6. CDK Inhibitors to Treat HER2+ Breast Cancer
7. CDK Inhibitors for the Treatment of Triple Negative Breast Cancer
8. TGFβ-Mediated Resistance to CDK Inhibitors
9. Future Directions: TGFβ and CDK Inhibitors in the Breast Cancer Microenvironment
10. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33. [Google Scholar] [CrossRef] [PubMed]
- DeSantis, C.E.; Ma, J.; Gaudet, M.M.; Newman, L.A.; Mph, K.D.M.; Sauer, A.G.; Jemal, A.; Siegel, R.L. Breast cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 438–451. [Google Scholar] [CrossRef] [PubMed]
- Bahrami, A.; Khazaei, M.; Shahidsales, S.; Hassanian, S.M.; Hasanzadeh, M.; Maftouh, M.; Ferns, G.A.; Avan, A. The therapeutic potential of PI3K/Akt/mTOR inhibitors in breast cancer: Rational and progress. J. Cell. Biochem. 2017, 119, 213–222. [Google Scholar] [CrossRef] [PubMed]
- Avan, A.; Avan, A.; Maftouh, M.; Mobarhan, M.G.; Shahidsales, S.; Gholamin, S. Biomarker analysis in CLEOPATRA: Searching for a sensitive prognostic factor in breast cancer. J. Clin. Oncol. 2015, 33, 1711–1712. [Google Scholar] [CrossRef]
- Liedtke, C.; Kolberg, H.-C. Systemic therapy of advanced/metastatic breast cancer—Current evidence and future concepts. Breast Care 2016, 11, 275–281. [Google Scholar] [CrossRef] [Green Version]
- Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; Harbeck, N. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 2020, 382, 810–821. [Google Scholar] [CrossRef]
- Schmid, P.; Cortes, J.; Bergh, J.C.; Pusztai, L.; Denkert, C.; Verma, S.; McArthur, H.L.; Kummel, S.; Ding, Y.; Karantza, V. KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs. placebo + chemo as neoadjuvant therapy followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC). Am. Soc. Clin. Oncol. 2018, 36. [Google Scholar] [CrossRef]
- Robson, M.; Im, S.A.; Senkus, E.; Xu, B.; Domchek, S.M.; Masuda, N.; Delaloge, S.; Li, W.; Tung, N.; Armstrong, A. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 2017, 377, 523–533. [Google Scholar] [CrossRef]
- Tang, Y.; Wang, Y.; Kiani, M.F.; Wang, B. Classification, treatment strategy, and associated drug resistance in breast cancer. Clin. Breast Cancer 2016, 16, 335–343. [Google Scholar] [CrossRef]
- Buck, M.B.; Knabbe, C. TGF-beta signaling in breast cancer. Ann. N. Y. Acad. Sci. 2006, 1089, 119–126. [Google Scholar] [CrossRef]
- Moses, H.; Barcellos-Hoff, M.H. TGF-β biology in mammary development and breast cancer. Cold Spring Harb. Perspect. Biol. 2011, 3, a003277. [Google Scholar] [CrossRef] [Green Version]
- Silberstein, G.B.; Daniel, C.W.J.S. Reversible inhibition of mammary gland growth by transforming growth factor-β. Science 1987, 237, 291–293. [Google Scholar] [CrossRef]
- Zhao, Y.; Ma, J.; Fan, Y.; Wang, Z.; Tian, R.; Jing, M.; Zhang, F.; Niu, R. TGF-β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways. Mol. Oncol. 2018, 12, 305–321. [Google Scholar] [CrossRef]
- Knabbe, C.; Lippman, M.E.; Wakefield, L.M.; Flanders, K.C.; Kasid, A.; Derynck, R.; Dickson, R.B. Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells. Cell 1987, 48, 417–428. [Google Scholar] [CrossRef]
- Roberts, A.B.; Sporn, M.B. Physiological actions and clinical applications of transforming growth factor-β (TGF-β). Growth Factors 1993, 8, 1–9. [Google Scholar] [CrossRef]
- Robertson, I.B.; Rifkin, D.B. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb. Perspect. Biol. 2016, 8, a021907. [Google Scholar] [CrossRef]
- Colak, S.; Ten Dijke, P. Targeting TGF-β signaling in cancer. Trends Cancer 2017, 3, 56–71. [Google Scholar] [CrossRef]
- Peng, D.; Fu, L.; Sun, G. Expression analysis of the TGF-β/SMAD target genes in adenocarcinoma of esophagogastric junctio. Open Med. 2016, 11, 83–86. [Google Scholar] [CrossRef] [Green Version]
- Heldin, C.H.; Moustakas, A. Role of Smads in TGFβ signaling. Cell Tissue Res. 2012, 347, 21–36. [Google Scholar] [CrossRef]
- Mu, Y.; Gudey, S.K.; Landström, M. Non-Smad signaling pathways. Cell Tissue Res. 2012, 347, 11–20. [Google Scholar] [CrossRef]
- Luo, K. Signaling cross talk between TGF-β/Smad and other signaling pathways. Cold Spring Harb. Perspect. Biol. 2017, 9, a022137. [Google Scholar] [CrossRef] [Green Version]
- Flanders, K.C.; Wakefield, L.M. Transforming growth factor-βs and mammary gland involution; functional roles and implications for cancer progression. J. Mammary Gland. Biol. Neoplasia 2009, 14, 131–144. [Google Scholar] [CrossRef] [Green Version]
- Liu, X.; Sun, Y.; Constantinescu, S.N.; Karam, E.; Weinberg, R.A.; Lodish, H.F. Transforming growth factor β-induced phosphorylation of Smad3 is required for growth inhibition and transcriptional induction in epithelial cells. Proc. Natl. Acad. Sci. USA 1997, 94, 10669–10674. [Google Scholar] [CrossRef] [Green Version]
- Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003, 36, 131–149. [Google Scholar] [CrossRef]
- Carnero, A.; Hannon, G. The INK4 family of CDK inhibitors. Cyclin Depend. Kinase (CDK) Inhib. 1998, 227, 43–55. [Google Scholar]
- Xiong, Y.; Hannon, G.J.; Zhang, H.; Casso, D.; Kobayashi, R.; Beach, D. p21 is a universal inhibitor of cyclin kinases. Nature 1993, 366, 701–704. [Google Scholar] [CrossRef]
- He, G.; Siddik, Z.H.; Huang, Z.; Wang, R.; Koomen, J.; Kobayashi, R.; Khokhar, A.R.; Kuang, J. Induction of p21 by p53 following DNA damage inhibits both Cdk4 and Cdk2 activities. Oncogene 2005, 24, 2929–2943. [Google Scholar] [CrossRef] [Green Version]
- Matsuura, I.; Denissova, N.G.; Wang, G.; He, D.; Long, J.; Liu, F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 2004, 430, 226–231. [Google Scholar] [CrossRef]
- Attisano, L.; Lee-Hoeflich, S.T. The smads. Genome Biol. 2001, 2, 1–8. [Google Scholar] [CrossRef]
- Gao, S.; Alarcón, C.; Sapkota, G.; Rahman, S.; Chen, P.Y.; Goerner, N.; Macias, M.J.; Erdjument-Bromage, H.; Tempst, P.; Massagué, J. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol. Cell 2009, 36, 457–468. [Google Scholar] [CrossRef] [Green Version]
- Kretzschmar, M.; Doody, J.; Timokhina, I.; Massagué, J. A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras. Genes Dev. 1999, 13, 804–816. [Google Scholar] [CrossRef] [PubMed]
- Mori, S.; Matsuzaki, K.; Yoshida, K.; Furukawa, F.; Tahashi, Y.; Yamagata, H.; Sekimoto, G.; Seki, T.; Matsui, H.; Nishizawa, M. TGF-β and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions. Oncogene 2004, 23, 7416–7429. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Furukawa, F.; Matsuzaki, K.; Mori, S.; Tahashi, Y.; Yoshida, K.; Sugano, Y.; Yamagata, H.; Matsushita, M.; Seki, T.; Inagaki, Y. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology 2003, 38, 879–889. [Google Scholar] [CrossRef] [PubMed]
- Buckley, M.F.; Sweeney, K.J.; Hamilton, J.A.; Sini, R.L.; Manning, D.L.; Nicholson, R.I.; Watts, C.; Musgrove, E.; Sutherland, R. Expression and amplification of cyclin genes in human breast cancer. Oncogene 1993, 8, 2127–2133. [Google Scholar]
- Hui, R.; Macmillan, R.D.; Kenny, F.S.; Musgrove, E.A.; Blamey, R.W.; Nicholson, R.I.; Robertson, J.F.; Sutherland, R.L. INK4a gene expression and methylation in primary breast cancer: Overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin. Cancer Res. 2000, 6, 2777–2787. [Google Scholar]
- Finn, R.S.; Dering, J.; Conklin, D.; Kalous, O.; Cohen, D.J.; Desai, A.J.; Ginther, C.; Atefi, M.; Chen, I.; Fowst, C. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009, 11, 1–13. [Google Scholar] [CrossRef] [Green Version]
- Thangavel, C.; Dean, J.L.; Ertel, A.; Knudsen, K.E.; Aldaz, C.M.; Witkiewicz, A.K.; Clarke, R.; Knudsen, E.S. Therapeutically activating RB: Reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr.-Relat. Cancer 2011, 18, 333–345. [Google Scholar] [CrossRef]
- Zwijsen, R.M.; Wientjens, E.; Klompmaker, R.; van der Sman, J.; Bernards, R.; Michalides, R.J. CDK-independent activation of estrogen receptor by cyclin D1. Cell 1997, 88, 405–415. [Google Scholar] [CrossRef] [Green Version]
- Zhang, M.; Zhang, L.; Hei, R.; Li, X.; Cai, H.; Wu, X.; Zheng, Q.; Cai, C. CDK inhibitors in cancer therapy, an overview of recent development. Am. J. Cancer Res. 2021, 11, 1913. [Google Scholar]
- Finn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.A.; Gelmon, K.; Harbeck, N.; Lipatov, O.N.; Walshe, J.M.; Moulder, S.; et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 2016, 375, 1925–1936. [Google Scholar] [CrossRef]
- Cristofanilli, M.; Turner, N.C.; Bondarenko, I.; Ro, J.; Im, S.A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016, 17, 425–439. [Google Scholar]
- Turner, N.C.; Slamon, D.J.; Ro, J.; Bondarenko, I.; Im, S.A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N. Engl. J. Med. 2018, 379, 1926–1936. [Google Scholar] [CrossRef]
- Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Blackwell, K.L.; André, F.; Winer, E.P. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 2016, 375, 1738–1748. [Google Scholar] [CrossRef]
- Kim, T.Y.; Kim, G.M.; Martín, M.; Zielinski, C.; Ruíz-borrego, M.; Carrasco, E.; Ciruelos, E.; Bermejo, B.; Margeli, M.; Turner, N.C.; et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J. Clin. Oncol. 2019, 37, 32–45. [Google Scholar]
- Tripathy, D.; Im, S.A.; Colleoni, M.; Franke, F.; Bardia, A.; Harbeck, N.; Hurvitz, S.A.; Chow, L.; Sohn, J.; Lee, K.S.; et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): A randomised phase 3 trial. Lancet Oncol. 2018, 19, 904–915. [Google Scholar] [CrossRef]
- Slamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; De Laurentiis, M.; Im, S.A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín, M.; et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N. Engl. J. Med. 2020, 382, 514–524. [Google Scholar] [CrossRef]
- Im, S.A.; Lu, Y.S.; Bardia, A.; Harbeck, N.; Colleoni, M.; Franke, F.; Chow, L.; Sohn, J.; Lee, K.-S.; Campos-Gomez, S.; et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N. Engl. J. Med. 2019, 381, 307–316. [Google Scholar] [CrossRef]
- Sledge, G.W., Jr.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P.A.; et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 2017, 35, 2875–2884. [Google Scholar] [CrossRef]
- Goetz, M.P.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.H.; Trédan, O.; Chen, S.-C.; Manso, L. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 2017, 35, 3638–3646. [Google Scholar] [CrossRef]
- Sledge, G.W.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P.A.; et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: A randomized clinical trial. JAMA Oncol. 2020, 6, 116–124. [Google Scholar] [CrossRef]
- Scott, S.C.; Lee, S.S.; Abraham, J. Mechanisms of therapeutic CDK4/6 inhibition in breast cancer. Semin. Oncol. 2017, 44, 385–394. [Google Scholar] [CrossRef]
- Bjornstrom, L.; Sjoberg, M. Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 2005, 19, 833–842. [Google Scholar] [CrossRef] [Green Version]
- Malek, D.; Gust, R.; Kleuser, B. 17-β-estradiol inhibits transforming-growth-factor-β-induced MCF-7 cell migration by Smad3-repression. Eur. J. Pharmacol. 2006, 534, 39–47. [Google Scholar] [CrossRef]
- Cherlet, T.; Murphy, L.C. Estrogen receptors inhibit Smad3 transcriptional activity through Ap-1 transcription factors. Mol. Cell. Biochem. 2007, 306, 33–42. [Google Scholar] [CrossRef]
- Ito, I.; Hanyu, A.; Wayama, M.; Goto, N.; Katsuno, Y.; Kawasaki, S.; Nakajima, Y.; Kajiro, M.; Komatsu, Y.; Fujimura, A.; et al. Estrogen inhibits transforming growth factor β signaling by promoting Smad2/3 degradation. J. Biol. Chem. 2010, 285, 14747–14755. [Google Scholar] [CrossRef] [Green Version]
- Li, Q.; Wu, L.; Oelschlager, D.K.; Wan, M.; Stockard, C.R.; Grizzle, W.E.; Wang, N.; Chen, H.; Sun, Y.; Cao, X. Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-α-positive breast cancer cells. J. Biol. Chem. 2005, 280, 27022–27028. [Google Scholar] [CrossRef] [Green Version]
- Tolaney, S.M.; Wardley, A.M.; Zambelli, S.; Hilton, J.F.; Troso-Sandoval, T.A.; Ricci, F.; Im, S.-A.; Kim, S.-B.; Johnston, S.R.; Chan, A.; et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): A randomised, open-label, phase 2 trial. Lancet Oncol. 2020, 21, 763–775. [Google Scholar] [CrossRef]
- Huang, F.; Shi, Q.; Li, Y.; Xu, L.; Xu, C.; Chen, F.; Wang, H.; Liao, H.; Chang, Z.; Liu, F.; et al. HER2/EGFR–AKT signaling switches TGFβ from inhibiting cell proliferation to promoting cell migration in breast cancer. Cancer Res. 2018, 78, 6073–6085. [Google Scholar] [CrossRef] [Green Version]
- Scaltriti, M.; Eichhorn, P.J.; Cortés, J.; Prudkin, L.; Aura, C.; Jiménez, J.; Chandarlapaty, S.; Serra, V.; Prat, A.; Ibrahim, Y.H.; et al. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl. Acad. Sci. USA 2011, 108, 3761–3766. [Google Scholar] [CrossRef] [Green Version]
- Decker, J.T.; Kandagatla, P.; Wan, L.; Bernstein, R.; Ma, J.A.; Shea, L.D.; Jeruss, J.S. Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer. Cancer Biol. Ther. 2020, 21, 994–1004. [Google Scholar] [CrossRef]
- Rakha, E.A.; Abd El-Rehim, D.; Paish, C.; Green, A.R.; Lee, A.H.; Robertson, J.F.; Blamey, R.W.; Macmillan, D.; Ellis, I.O. Basal phenotype identifies a poor prognostic subgroup of breast cancer of clinical importance. Eur. J. Cancer 2006, 42, 3149–3156. [Google Scholar] [CrossRef] [PubMed]
- Koboldt, D.C.F.R.; Fulton, R.; McLellan, M.; Schmidt, H.; Kalicki-Veizer, J.; McMichael, J.; Fulton, L.; Dooling, D.; Ding, L.; Mardis, E.; et al. Comprehensive molecular portraits of human breast tumours. Nature 2012, 490, 61–70. [Google Scholar]
- Rao, S.S.; Bushnell, G.G.; Azarin, S.M.; Spicer, G.; Aguado, B.A.; Stoehr, J.R.; Jiang, E.J.; Backman, V.; Shea, L.D.; Jeruss, J.S. Enhanced survival with implantable scaffolds that capture metastatic breast cancer cells in vivo. Cancer Res. 2016, 76, 5209–5218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tarasewicz, E.; Hamdan, R.; Straehla, J.; Hardy, A.; Nunez, O.; Zelivianski, S.; Dokic, D.; Jeruss, J.S. CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and surviving. Cancer Biol. Ther. 2014, 15, 1301–1311. [Google Scholar] [CrossRef] [Green Version]
- Tarasewicz, E.; Rivas, L.; Hamdan, R.; Dokic, D.; Parimi, V.; Bernabe, B.P.; Thomas, A.; Shea, L.D.; Jeruss, J.S. Inhibition of CDK-mediated phosphorylation of Smad3 results in decreased oncogenesis in triple negative breast cancer cells. Cell Cycle 2014, 13, 3191–3201. [Google Scholar] [CrossRef] [Green Version]
- Hu, Y.; Gao, J.; Wang, M.; Li, M. Potential prospect of CDK4/6 inhibitors in triple-negative breast cancer. Cancer Manag. Res. 2021, 13, 5223. [Google Scholar] [CrossRef]
- Tarasewicz, E.; Jeruss, J.S. Phospho-specific Smad3 signaling: Impact on breast oncogenesis. Cell Cycle 2012, 11, 2443–2451. [Google Scholar] [CrossRef] [Green Version]
- Horiuchi, D.; Kusdra, L.; Huskey, N.E.; Chandriani, S.; Lenburg, M.; Gonzalez-Angulo, A.M.; Creasman, K.J.; Bazarov, A.V.; Smyth, J.; Davis, S.E.; et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J. Exp. Med. 2012, 209, 679–696. [Google Scholar] [CrossRef] [Green Version]
- Thomas, A.L.; Lind, H.; Hong, A.; Dokic, D.; Oppat, K.; Rosenthal, E.; Guo, A.; Thomas, A.; Hamden, R.; Jeruss, J.S. Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells. Cell Cycle 2017, 16, 1453–1464. [Google Scholar] [CrossRef] [Green Version]
- Matsuura, I.; Chiang, K.N.; Lai, C.Y.; He, D.; Wang, G.; Ramkumar, R.; Uchida, T.; Ryo, A.; Lu, K.; Liu, F. Pin1 promotes transforming growth factor-β-induced migration and invasion. J. Biol. Chem. 2010, 285, 1754–1764. [Google Scholar] [CrossRef] [Green Version]
- Nakano, A.; Koinuma, D.; Miyazawa, K.; Uchida, T.; Saitoh, M.; Kawabata, M.; Hanai, J.-I.; Akiyama, H.; Abe, M.; Miyazono, K.; et al. Pin1 Down-regulates Transforming Growth Factor-β (TGF-β) signaling by inducing degradation of Smad proteins. J. Biol. Chem. 2009, 284, 6109–6115. [Google Scholar] [CrossRef] [Green Version]
- Yu, Q.; Geng, Y.; Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 2001, 411, 1017–1021. [Google Scholar] [CrossRef]
- Li, Z.; Zou, W.; Zhang, J.; Zhang, Y.; Xu, Q.; Li, S.; Chen, C. Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer. Front. Pharmacol. 2020, 11, 1723. [Google Scholar] [CrossRef]
- Dean, J.L.; Thangavel, C.; McClendon, A.K.; Reed, C.A.; Knudsen, E.S. Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene 2010, 29, 4018–4032. [Google Scholar] [CrossRef] [Green Version]
- Dean, J.L.; McClendon, A.K.; Hickey, T.E.; Butler, L.M.; Tilley, W.D.; Witkiewicz, A.K.; Knudsen, E. S Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 2012, 11, 2756–2761. [Google Scholar] [CrossRef]
- Malorni, L.; Piazza, S.; Ciani, Y.; Guarducci, C.; Bonechi, M.; Biagioni, C.; Hart, C.D.; Verardo, R.; Di Leo, A.; Migliaccio, I. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 2016, 7, 68012–68022. [Google Scholar] [CrossRef] [Green Version]
- Herrera-Abreu, M.T.; Palafox, M.; Asghar, U.; Rivas, M.A.; Cutts, R.J.; Garcia-Murillas, I.; Pearson, A.; Guzman, M.; Rodriguez, O.; Grueso, J.; et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor–positive breast cancer. Cancer Res. 2016, 76, 2301–2313. [Google Scholar] [CrossRef] [Green Version]
- Taylor-Harding, B.; Aspuria, P.J.; Agadjanian, H.; Cheon, D.J.; Mizuno, T.; Greenberg, D.; Allen, J.R.; Spurka, L.; Funari, V.; Spiteri, E.; et al. Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS. Oncotarget 2015, 6, 696. [Google Scholar] [CrossRef] [Green Version]
- Pandey, K.; Park, N.; Park, K.S.; Hur, J.; Cho, Y.B.; Kang, M.; An, H.-J.; Kim, S.; Hwang, S.; Moon, Y.W. Combined CDK2 and CDK4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers 2020, 12, 3566. [Google Scholar] [CrossRef]
- Pardali, K.; Kurisaki, A.; Morén, A.; Ten Dijke, P.; Kardassis, D.; Moustakas, A. Role of Smad proteins and transcription factor Sp1 in p21Waf1/Cip1 regulation by transforming growth factor-β. J. Biol. Chem. 2000, 275, 29244–29256. [Google Scholar] [CrossRef] [Green Version]
- Filipits, M.; Dafni, U.; Gnant, M.; Polydoropoulou, V.; Hills, M.; Kiermaier, A.; De Azambuja, E.; Larsimont, D.; Rojo, F.; Viale, G.; et al. Association of p27 and cyclin D1 expression and benefit from adjuvant trastuzumab treatment in HER2-positive early breast cancer: A TransHERA study. Clin. Cancer Res. 2018, 24, 3079–3086. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.E.; Xiang, B.; Guix, M.; Olivares, M.G.; Parker, J.; Chung, C.H.; Pandiella, A.; Arteaga, C.L. Transforming growth factor β engages TACE and ErbB3 to activate phosphatidylinositol-3 kinase/Akt in ErbB2-overexpressing breast cancer and desensitizes cells to trastuzumab. Mol. Cell. Biol. 2008, 28, 5605–5620. [Google Scholar] [CrossRef] [Green Version]
- Keyomarsi, K.; Tucker, S.L.; Buchholz, T.A.; Callister, M.; Ding, Y.E.; Hortobagyi, G.N.; Bedrosian, I.; Knickerbocker, C.; Toyofuku, W.; Lowe, M.; et al. Cyclin E and survival in patients with breast cancer. N. Engl. J. Med. 2002, 347, 1566–1575. [Google Scholar] [CrossRef]
- Joffroy, C.M.; Buck, M.B.; Stope, M.B.; Popp, S.L.; Pfizenmaier, K.; Knabbe, C. Antiestrogens induce transforming growth factor β–mediated immunosuppression in breast cancer. Cancer Res. 2010, 70, 1314–1322. [Google Scholar] [CrossRef] [Green Version]
- Rong, L.; Li, R.; Li, S.; Luo, R. Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells. Oncol. Lett. 2016, 11, 500–504. [Google Scholar] [CrossRef] [Green Version]
- De Martino, M.; Daviaud, C.; Diamond, J.M.; Kraynak, J.; Alard, A.; Formenti, S.C.; Miller, L.D.; DeMaria, S.; Vanpouille-Box, C. Activin a promotes regulatory T-cell–mediated immunosuppression in irradiated breast cancer. Cancer Immunol. Res. 2021, 9, 89–102. [Google Scholar] [CrossRef]
- Guido, C.; Whitaker-Menezes, D.; Capparelli, C.; Balliet, R.; Lin, Z.; Pestell, R.G.; Howell, A.; Aquila, S.; Andò, S.; Martinez-Outschoorn, U.; et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: Connecting TGF-β signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle 2012, 11, 3019–3035. [Google Scholar] [CrossRef] [Green Version]
- Yu, Y.; Xiao, C.-H.; Tan, L.-D.; Wang, Q.-S.; Li, X.-Q.; Feng, Y.-M. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J. Cancer 2014, 110, 724–732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chakravarthy, A.; Khan, L.; Bensler, N.P.; Bose, P.; De Carvalho, D.D. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat. Commun. 2018, 9, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Zhang, F.; Wang, H.; Wang, X.; Jiang, G.; Liu, H.; Zhang, G.; Wang, H.; Fang, R.; Bu, X.; Cai, S.; et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 2016, 7, 52294–52306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cai, J.; Xia, L.; Li, J.; Ni, S.; Song, H.; Wu, X. Tumor-associated macrophages derived TGF-β‒induced epithelial to mesenchymal transition in colorectal cancer cells through Smad2, 3-4/Snail signaling pathway. Cancer Res. Treat. Off. J. Korean Cancer Assoc. 2019, 51, 252. [Google Scholar]
- Laoui, D.; Movahedi, K.; Van Overmeire, E.; Bossche, J.V.D.; Schouppe, E.; Mommer, C.; Nikolaou, A.; Morias, Y.; De Baetselier, P.; Van Ginderachter, J. Tumor-associated macrophages in breast cancer: Distinct subsets, distinct functions. Int. J. Dev. Biol. 2011, 55, 861–867. [Google Scholar] [CrossRef]
- Li, M.O.; Sanjabi, S.; Flavell, R.A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and-independent mechanisms. Immunity 2006, 25, 455–471. [Google Scholar] [CrossRef] [Green Version]
- Ghiringhelli, F.; Ménard, C.; Terme, M.; Flament, C.; Taieb, J.; Chaput, N.; Puig, P.E.; Novault, S.; Escudier, B.; Vivier, E.; et al. CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner. J. Exp. Med. 2005, 202, 1075–1085. [Google Scholar] [CrossRef]
- Liu, F.; Lang, R.; Zhao, J.; Zhang, X.; Pringle, G.A.; Fan, Y.; Yin, D.; Gu, F.; Yao, Z.; Fu, L. CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res. Treat. 2011, 130, 645–655. [Google Scholar] [CrossRef]
- Oshi, M.; Asaoka, M.; Tokumaru, Y.; Angarita, F.A.; Yan, L.; Matsuyama, R.; Zsiros, E.; Ishikawa, T.; Endo, I.; Takabe, K. Abundance of regulatory T cell (Treg) as a predictive biomarker for neoadjuvant chemotherapy in triple-negative breast cancer. Cancers 2020, 12, 3038. [Google Scholar] [CrossRef]
- Solis-Castillo, L.A.; Garcia-Romo, G.S.; Diaz-Rodriguez, A.; Reyes-Hernandez, D.; Tellez-Rivera, E.; Rosales-Garcia, V.H.; Mendez-Cruz, A.R.; Jimenez-Flores, J.R.; Villafana-Vazquez, V.H.; Pedroza-Gonzalez, A. Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer. Breast Cancer 2020, 27, 837–849. [Google Scholar] [CrossRef]
- Baas, M.; Besançon, A.; Goncalves, T.; Valette, F.; Yagita, H.; Sawitzki, B.; Volk, H.-D.; Waeckel-Enée, E.; Rocha, B.; Chatenoud, L.; et al. TGFβ-dependent expression of PD-1 and PD-L1 controls CD8+ T cell anergy in transplant tolerance. eLife 2016, 5, e08133. [Google Scholar] [CrossRef]
- Coffelt, S.B.; Kersten, K.; Doornebal, C.W.; Weiden, J.; Vrijland, K.; Hau, C.-S.; Verstegen, N.J.M.; Ciampricotti, M.; Hawinkels, L.J.A.C.; Jonkers, J.; et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015, 522, 345–348. [Google Scholar] [CrossRef]
- Martins-Cardoso, K.; Almeida, V.H.; Bagri, K.M.; Rossi, M.I.D.; Mermelstein, C.S.; König, S.; Monteiro, R.Q. Neutrophil extra-cellular traps (Nets) promote pro-metastatic phenotype in human breast cancer cells through epithelial–mesenchymal transi-tion. Cancers 2020, 12, 1542. [Google Scholar] [CrossRef]
- Park, J.; Wysocki, R.W.; Amoozgar, Z.; Maiorino, L.; Fein, M.R.; Jorns, J.; Schott, A.F.; Kinugasa-Katayama, Y.; Lee, Y.; Won, N.H.; et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl. Med. 2016, 8, 361ra138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wculek, S.; Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 2015, 528, 413–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xiao, Y.; Cong, M.; Li, J.; He, D.; Wu, Q.; Tian, P.; Wang, Y.; Yang, S.; Liang, C.; Liang, Y.; et al. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. Cancer Cell 2021, 39, 423–437. [Google Scholar] [CrossRef] [PubMed]
- Oakes, R.S.; Bushnell, G.G.; Orbach, S.M.; Kandagatla, P.; Zhang, Y.; Morris, A.H.; Hall, M.S.; Lafaire, P.; Decker, J.T.; Hartfield, R.M.; et al. Metastatic conditioning of myeloid cells at a subcutaneous synthetic niche reflects disease progression and predicts therapeutic outcomes. Cancer Res. 2010, 80, 602–612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alizadeh, D.; Trad, M.; Hanke, N.T.; Larmonier, C.B.; Janikashvili, N.; Bonnotte, B.; Katsanis, E.; Larmonier, N. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014, 74, 104–118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Di Micco, R.; Krizhanovsky, V.; Baker, D.; di Fagagna, F.D. Cellular senescence in ageing: From mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 2020, 22, 75–95. [Google Scholar] [CrossRef] [PubMed]
- Coppé, J.-P.; Desprez, P.-Y.; Krtolica, A.; Campisi, J. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annu. Rev. Pathol. Mech. Dis. 2010, 5, 99–118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bai, X.; Yi, M.; Jiao, Y.; Chu, Q.; Wu, K. Blocking TGF-β signaling to enhance the efficacy of immune checkpoint inhibitor. OncoTargets Ther. 2019, 12, 9527–9538. [Google Scholar] [CrossRef] [Green Version]
- Martin, C.J.; Datta, A.; Littlefield, C.; Kalra, A.; Chapron, C.; Wawersik, S.; Dagbay, K.B.; Brueckner, C.T.; Nikiforov, A.; Danehy, F.T.; et al. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci. Transl. Med. 2020, 12, eaay8456. [Google Scholar] [CrossRef]
- Terabe, M.; Robertson, F.C.; Clark, K.; De Ravin, E.; Bloom, A.; Venzon, D.J.; Kato, S.; Mirza, A.; Berzofsky, J.A. Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. Oncoimmunology 2017, 6, e1308616. [Google Scholar] [CrossRef] [Green Version]
- Deng, J.; Wang, E.S.; Jenkins, R.W.; Li, S.; Dries, R.; Yates, K.; Chhabra, S.; Huang, W.; Liu, H.; Aref, A.R.; et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018, 8, 216–233. [Google Scholar] [CrossRef] [Green Version]
- Goel, S.; DeCristo, M.J.; Watt, A.C.; BrinJones, H.; Sceneay, J.; Li, B.B.; Khan, N.; Ubellacker, J.M.; Xie, S.; Metzger-Filho, O.; et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 2017, 548, 471–475. [Google Scholar] [CrossRef]
- Zhang, J.; Bu, X.; Wang, H.; Zhu, Y.; Geng, Y.; Nihira, N.T.; Tan, Y.; Ci, Y.; Wu, F.; Dai, X.; et al. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature 2018, 553, 91–95. [Google Scholar] [CrossRef] [Green Version]
- Hurvitz, S.A.; Martin, M.; Press, M.F.; Chan, D.; Fernandez-Abad, M.; Petru, E.; Rostorfer, R.; Guarneri, V.; Huang, C.-S.; Barriga, S.; et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+/HER2—Breast cancer. Clin. Cancer Res. 2019, 26, 566–580. [Google Scholar] [CrossRef] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Decker, J.T.; Ma, J.A.; Shea, L.D.; Jeruss, J.S. Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer. Cancers 2021, 13, 5343. https://doi.org/10.3390/cancers13215343
Decker JT, Ma JA, Shea LD, Jeruss JS. Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer. Cancers. 2021; 13(21):5343. https://doi.org/10.3390/cancers13215343
Chicago/Turabian StyleDecker, Joseph T., Jeffrey A. Ma, Lonnie D. Shea, and Jacqueline S. Jeruss. 2021. "Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer" Cancers 13, no. 21: 5343. https://doi.org/10.3390/cancers13215343