## 1 Introduction  
Increasing epidemiological evidence has highlighted that the exposure to environmental pollution can increase the risk of various diseases, including cancer [1; 2; 3; 4; 5; 6]; additionally, low-level pollutants have been shown to trigger cancer initiation and progression, and to promote tissue invasion, metastasis and chemoresistance [7; 8; 9]. Among the environmental toxicants, cigarette smoke (CS), both active and passive, is known to act as a promoting factor for the incidence of breast cancer, its aggressiveness, and recurrence [10; 11; 12; 13; 14; 15]. Moreover, the risk of breast cancer was found to be enhanced in susceptible subjects exposed to environmental smoke and to E-cigarettes [16; 17; 18; 19]. Although little is still known about the role of tobacco carcinogens in breast cancer progression and metastasis, nicotine seems to play a pivotal role, since it is able to promote cell proliferation and angiogenesis by modulating different cascades, which in turn control the expression of proapoptotic and antiapoptotic factors [3; 20]. Moreover, it induces an immune-mediated inflammatory response through the regulation of the genes involved in cancer cell proliferation and migration [21]. Nicotine also seems to contribute to the chemoresistance induced by CS, likely inducing oxidative stress and the overexpression of the ATP-binding cassette (ABC) proteins [22; 23; 24; 25]. Along with nicotine, polycyclic aromatic hydrocarbons have been found able to reduce the effectiveness of anticancer drugs, by promoting their enzymatic degradation [25]. This strengthens the interest in developing possible protective strategies to limit the CS injury due to both active smoking and involuntary exposure. Among possible interventions, chemopre agents attracted great attention due to their ability to both prevent genotoxicity in healthy people and in highly susceptible subjects, and also to interfere with the proliferation and progression of pre-existing cancer, thus being able to support chemotherapy and to avoid relapses [26]. However, effective chemopre strategies against cigarette smoke are not currently available, and those against breast cancer are limited owing to their possible side effects [26; 27; 28; 29]. Recent evidence highlighted the interesting chemopreentive and chemo-sensitizing properties of the natural cryophyllene sesquiterpenes \(\beta\)-caryophyllene (Figure 1) and its metabolite \(\beta\)-caryophyllene oxide; particularly, they prevented the damage of different environmental pollutants, including cigarette smoke, nitroarenes and alkylating agents, and sensitized different cancer cells to chemotherapy both in vitro and in vivo [26; 30; 31; 32; 33]. Among chemopretive mechanisms, cryophyllene sesquiterpenes were able to interfere with DNA-damage, to modulate cell cycle progress and the cell redox state and inhibited the activation of the signal transducer and activator of transcription 3 (STAT3) pathway, thus in turn regulating the apoptotic cell death [26; 32]. \(\beta\)-Caryophyllene also exhibited antiproliferative properties in triple negative breast cancer cells and modulated the expression of CB2 receptors [26; 30; 31]. In line with this evidence and in order to discover potential strategies to limit the harmful effect of smoke, in the present study we evaluated the ability of \(\beta\)-caryophyllene to counteract the chemoresistance induced by cigarette smoke condensate (CSC) in MDA-MB-468 triple-negative breast cancer cells. This cancer cell model was chosen due to the high risk of chemoresistance found in patients with triple-negative breast cancer and the associated aggressiveness and poor prognosis [34]. Different cell processes accounting for triple-negative breast cancer cell proliferation and progression, and probably responsible for chemoresistance, including autophagic/apoptotic cell death, oxidative stress, genomic instability, cell cycle progression and cell migration, were evaluated.